TY  - JOUR
A1  - Seifert, Annika
A1  - Groll, Jürgen
A1  - Weichhold, Jan
A1  - Boehm, Anne V.
A1  - Müller, Frank A.
A1  - Gbureck, Uwe
T1  - Phase Conversion of Ice‐Templated α‐Tricalcium Phosphate Scaffolds into Low‐Temperature Calcium Phosphates with Anisotropic Open Porosity
JF  - Advanced Engineering Materials
N2  - The current study aims to extend the material platform for anisotropically structured calcium phosphates to low-temperature phases such as calcium-deficient hydroxyapatite (CDHA) or the secondary phosphates monetite and brushite. This is achieved by the phase conversion of highly porous α-tricalcium phosphate (α-TCP) scaffolds fabricated by ice-templating into the aforementioned phases by hydrothermal treatment or incubation in phosphoric acid. Prior to these steps, α-TCP scaffolds are either sintered for 8 h at 1400 °C or remain in their original state. Both nonsintered and sintered α-TCP specimens are converted into CDHA by hydrothermal treatment, while a transformation into monetite and brushite is achieved by incubation in phosphoric acid. Hydrothermal treatment for 72 h at 175 °C increases the porosity in nonsintered samples from 85% to 88% and from 75% to 88% in the sintered ones. An increase in the specific surface area from (1.102 ± 0.005) to (9.17 ± 0.01) m2 g−1 and from (0.190 ± 0.004) to (2.809 ± 0.002) m2 g−1 due to the phase conversion is visible for both the nonsintered and sintered samples. Compressive strength of the nonsintered samples increases significantly from (0.76 ± 0.11) to (5.29 ± 0.94) MPa due to incubation in phosphoric acid.
KW  - phase conversion
KW  - α-tricalcium phosphate
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-256311
VL  - 23
IS  - 5
ER  - 
TY  - JOUR
A1  - Fiedler, Mascha O.
A1  - Muellenbach, Ralf M.
A1  - Rolfes, Caroline
A1  - Lotz, Christopher
A1  - Nickel, Felix
A1  - Müller-Stich, Beat P.
A1  - Supady, Alexander
A1  - Lepper, Philipp M.
A1  - Weigand, Markus A.
A1  - Meybohm, Patrick
A1  - Kalenka, Armin
A1  - Reyher, Christian
T1  - Pumpless extracorporeal hemadsorption technique (pEHAT): a proof-of-concept animal study
JF  - Journal of Clinical Medicine
N2  - Background: Extracorporeal hemadsorption eliminates proinflammatory mediators in critically ill patients with hyperinflammation. The use of a pumpless extracorporeal hemadsorption technique allows its early usage prior to organ failure and the need for an additional medical device. In our animal model, we investigated the feasibility of pumpless extracorporeal hemadsorption over a wide range of mean arterial pressures (MAP). Methods: An arteriovenous shunt between the femoral artery and femoral vein was established in eight pigs. The hemadsorption devices were inserted into the shunt circulation; four pigs received CytoSorb\(^®\) and four Oxiris\(^®\) hemadsorbers. Extracorporeal blood flow was measured in a range between mean arterial pressures of 45–85 mmHg. Mean arterial pressures were preset using intravenous infusions of noradrenaline, urapidil, or increased sedatives. Results: Extracorporeal blood flows remained well above the minimum flows recommended by the manufacturers throughout all MAP steps for both devices. Linear regression resulted in CytoSorb\(^®\) blood flow [mL/min] = 4.226 × MAP [mmHg] − 3.496 (R-square 0.8133) and Oxiris\(^®\) blood flow [mL/min] = 3.267 × MAP [mmHg] + 57.63 (R-square 0.8708), respectively. Conclusion: Arteriovenous pumpless extracorporeal hemadsorption resulted in sufficient blood flows through both the CytoSorb\(^®\) and Oxiris\(^®\) devices over a wide range of mean arterial blood pressures and is likely an intriguing therapeutic option in the early phase of septic shock or hyperinflammatory syndromes.
KW  - blood purification
KW  - extracorporeal hemadsorption
KW  - cytokines
KW  - adsorption
KW  - animal model
KW  - immunosorbents
KW  - septic shock
KW  - endotoxin
KW  - extracorporeal techniques in hemadsorption therapy
KW  - arteriovenous extracorporeal hemadsorption technique
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297347
SN  - 2077-0383
VL  - 11
IS  - 22
ER  - 
TY  - JOUR
A1  - Müller, Jörg
A1  - Mitesser, Oliver
A1  - Schaefer, H. Martin
A1  - Seibold, Sebastian
A1  - Busse, Annika
A1  - Kriegel, Peter
A1  - Rabl, Dominik
A1  - Gelis, Rudy
A1  - Arteaga, Alejandro
A1  - Freile, Juan
A1  - Leite, Gabriel Augusto
A1  - de Melo, Tomaz Nascimento
A1  - LeBien, Jack
A1  - Campos-Cerqueira, Marconi
A1  - Blüthgen, Nico
A1  - Tremlett, Constance J.
A1  - Böttger, Dennis
A1  - Feldhaar, Heike
A1  - Grella, Nina
A1  - Falconí-López, Ana
A1  - Donoso, David A.
A1  - Moriniere, Jerome
A1  - Buřivalová, Zuzana
T1  - Soundscapes and deep learning enable tracking biodiversity recovery in tropical forests
JF  - Nature Communications
N2  - Tropical forest recovery is fundamental to addressing the intertwined climate and biodiversity loss crises. While regenerating trees sequester carbon relatively quickly, the pace of biodiversity recovery remains contentious. Here, we use bioacoustics and metabarcoding to measure forest recovery post-agriculture in a global biodiversity hotspot in Ecuador. We show that the community composition, and not species richness, of vocalizing vertebrates identified by experts reflects the restoration gradient. Two automated measures – an acoustic index model and a bird community composition derived from an independently developed Convolutional Neural Network - correlated well with restoration (adj-R² = 0.62 and 0.69, respectively). Importantly, both measures reflected composition of non-vocalizing nocturnal insects identified via metabarcoding. We show that such automated monitoring tools, based on new technologies, can effectively monitor the success of forest recovery, using robust and reproducible data.
KW  - animal behaviour
KW  - conservation biology
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-358130
VL  - 14
ER  - 
TY  - JOUR
A1  - Zottnick, Sven H.
A1  - Sprenger, Jan A. P.
A1  - Finze, Maik
A1  - Müller‐Buschbaum, Klaus
T1  - Statistic Replacement of Lanthanide Ions in Bis‐salicylatoborate Coordination Polymers for the Deliberate Control of the Luminescence Chromaticity
JF  - ChemistryOpen
N2  - Based on the strand‐like coordination polymer (CP) type \(^{1}\)\(_{∞}\)[Ln(BSB)\(_{3}\)(py)\(_{2}\)], [BSB]−=bis‐salicylatoborate anion, mixed Eu/Tb‐containing compounds of the constitution \(^{1}\)\(_{∞}\)[Eu\(_{x}\)Tb\(_{1-x}\)(BSB)\(_{3}\)(py)\(_{2}\)] were synthesised ionothermally for a phase width of (x=0.25–0.75) and characterized regarding structure and optical properties. Previously, known only for other lanthanides, the mixed 1D−Eu/Tb‐CPs show excellent options for statistic replacement of the Ln‐cations during synthesis yielding solid solutions. The products are highly luminescent, with the chromaticity being a direct function of the amount of the respective Ln‐ions. Corresponding to an overall addition of emission intensities, the green Tb\(^{3+}\) emission and the red Eu\(^{3+}\) emission allow for a chromaticity control that also includes yellow emission. Control of the luminescence colour renders them suitable examples of the versatility of statistic replacement of metal ions in coordination chemistry. In addition, crystallization of [EMIm]\(_{2}\)[YCl\(_{5}\)(py)] illuminates possible other products of the ionothermal reactions of [EMIm][BSB] with LnCl\(_{3}\) constituted by components not being part of the main CPs.
KW  - borates
KW  - coordination polymers
KW  - ionic liquids
KW  - lanthanides
KW  - luminescence
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239953
VL  - 10
IS  - 2
SP  - 164
EP  - 170
ER  - 
TY  - JOUR
A1  - Boschert, Verena
A1  - Teusch, Jonas
A1  - Aljasem, Anwar
A1  - Schmucker, Philipp
A1  - Klenk, Nicola
A1  - Straub, Anton
A1  - Bittrich, Max
A1  - Seher, Axel
A1  - Linz, Christian
A1  - Müller-Richter, Urs D. A.
A1  - Hartmann, Stefan
T1  - HGF-induced PD-L1 expression in head and neck cancer: preclinical and clinical findings
JF  - International Journal of Molecular Sciences
N2  - Head and neck squamous cell carcinoma (HNSCC) is a widespread disease with a low survival rate and a high risk of recurrence. Nowadays, immune checkpoint inhibitor (ICI) treatment is approved for HNSCC as a first-line treatment in recurrent and metastatic disease. ICI treatment yields a clear survival benefit, but overall response rates are still unsatisfactory. As shown in different cancer models, hepatocyte growth factor/mesenchymal–epithelial transition (HGF/Met) signaling contributes to an immunosuppressive microenvironment. Therefore, we investigated the relationship between HGF and programmed cell death protein 1 (PD-L1) expression in HNSCC cell lines. The preclinical data show a robust PD-L1 induction upon HGF stimulation. Further analysis revealed that the HGF-mediated upregulation of PD-L1 is MAP kinase-dependent. We then hypothesized that serum levels of HGF and soluble programmed cell death protein 1 (sPD-L1) could be potential markers of ICI treatment failure. Thus, we determined serum levels of these proteins in 20 HNSCC patients before ICI treatment and correlated them with treatment outcomes. Importantly, the clinical data showed a positive correlation of both serum proteins (HGF and sPD-L1) in HNSCC patient’s sera. Moreover, the serum concentration of sPD-L1 was significantly higher in ICI non-responsive patients. Our findings indicate a potential role for sPD-L1 as a prognostic marker for ICI treatment in HNSCC.
KW  - HNSCC
KW  - head and neck cancer
KW  - HGF
KW  - Met
KW  - PD-L1
KW  - immune therapy
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236220
SN  - 1422-0067
VL  - 21
IS  - 20
ER  - 
TY  - JOUR
A1  - Boschert, Verena
A1  - Teusch, Jonas
A1  - Müller-Richter, Urs D. A.
A1  - Brands, Roman C.
A1  - Hartmann, Stefan
T1  - PKM2 modulation in head and neck squamous cell carcinoma
JF  - International Journal of Molecular Sciences
N2  - The enzyme pyruvate kinase M2 (PKM2) plays a major role in the switch of tumor cells from oxidative phosphorylation to aerobic glycolysis, one of the hallmarks of cancer. Different allosteric inhibitors or activators and several posttranslational modifications regulate its activity. Head and neck squamous cell carcinoma (HNSCC) is a common disease with a high rate of recurrence. To find out more about PKM2 and its modulation in HNSCC, we examined a panel of HNSCC cells using real-time cell metabolic analysis and Western blotting with an emphasis on phosphorylation variant Tyr105 and two reagents known to impair PKM2 activity. Our results show that in HNSCC, PKM2 is commonly phosphorylated at Tyrosine 105. Its levels depended on tyrosine kinase activity, emphasizing the importance of growth factors such as EGF (epidermal growth factor) on HNSCC metabolism. Furthermore, its correlation with the expression of CD44 indicates a role in cancer stemness. Cells generally reacted with higher glycolysis to PKM2 activator DASA-58 and lower glycolysis to PKM2 inhibitor Compound 3k, but some were more susceptible to activation and others to inhibition. Our findings emphasize the need to further investigate the role of PKM2 in HNSCC, as it could aid understanding and treatment of the disease.
KW  - HNSCC
KW  - head and neck cancer
KW  - cancer metabolism
KW  - glycolysis
KW  - PKM2
KW  - Warburg effect
KW  - CD44
KW  - Compound 3k
KW  - DASA-58
KW  - AMPK
KW  - TXNIP
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284458
SN  - 1422-0067
VL  - 23
IS  - 2
ER  - 
TY  - JOUR
A1  - Doll, Julia
A1  - Vona, Barbara
A1  - Schnapp, Linda
A1  - Rüschendorf, Franz
A1  - Khan, Imran
A1  - Khan, Saadullah
A1  - Muhammad, Noor
A1  - Alam Khan, Sher
A1  - Nawaz, Hamed
A1  - Khan, Ajmal
A1  - Ahmad, Naseer
A1  - Kolb, Susanne M.
A1  - Kühlewein, Laura
A1  - Labonne, Jonathan D. J.
A1  - Layman, Lawrence C.
A1  - Hofrichter, Michaela A. H.
A1  - Röder, Tabea
A1  - Dittrich, Marcus
A1  - Müller, Tobias
A1  - Graves, Tyler D.
A1  - Kong, Il-Keun
A1  - Nanda, Indrajit
A1  - Kim, Hyung-Goo
A1  - Haaf, Thomas
T1  - Genetic Spectrum of Syndromic and Non-Syndromic Hearing Loss in Pakistani Families
JF  - Genes
N2  - The current molecular genetic diagnostic rates for hereditary hearing loss (HL) vary considerably according to the population background. Pakistan and other countries with high rates of consanguineous marriages have served as a unique resource for studying rare and novel forms of recessive HL. A combined exome sequencing, bioinformatics analysis, and gene mapping approach for 21 consanguineous Pakistani families revealed 13 pathogenic or likely pathogenic variants in the genes GJB2, MYO7A, FGF3, CDC14A, SLITRK6, CDH23, and MYO15A, with an overall resolve rate of 61.9%. GJB2 and MYO7A were the most frequently involved genes in this cohort. All the identified variants were either homozygous or compound heterozygous, with two of them not previously described in the literature (15.4%). Overall, seven missense variants (53.8%), three nonsense variants (23.1%), two frameshift variants (15.4%), and one splice-site variant (7.7%) were observed. Syndromic HL was identified in five (23.8%) of the 21 families studied. This study reflects the extreme genetic heterogeneity observed in HL and expands the spectrum of variants in deafness-associated genes.
KW  - genetic diagnosis
KW  - consanguinity
KW  - genome-wide linkage analysis
KW  - hearing loss
KW  - Pakistan
KW  - exome sequencing
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-219293
SN  - 2073-4425
VL  - 11
IS  - 11
ER  - 
TY  - JOUR
A1  - Stein, Kiera
A1  - Maruf, Abdullah Al
A1  - Müller, Daniel J.
A1  - Bishop, Jeffrey R.
A1  - Bousman, Chad A.
T1  - Serotonin transporter genetic variation and antidepressant response and tolerability: a systematic review and meta-analysis
JF  - Journal of Personalized Medicine
N2  - Antidepressants are used to treat several psychiatric disorders; however, a large proportion of patients do not respond to their first antidepressant therapy and often experience adverse drug reactions (ADR). A common insertion–deletion polymorphism in the promoter region (5-HTTLPR) of the serotonin transporter (SLC6A4) gene has been frequently investigated for its association with antidepressant outcomes. Here, we performed a systematic review and meta-analysis to assess 5-HTTLPR associations with antidepressants: (1) response in psychiatric disorders other than major depressive disorder (MDD) and (2) tolerability across all psychiatric disorders. Literature searches were performed up to January 2021, yielding 82 studies that met inclusion criteria, and 16 of these studies were included in the meta-analyses. Carriers of the 5-HTTLPR LL or LS genotypes were more likely to respond to antidepressant therapy, compared to the SS carriers in the total and European ancestry-only study populations. Long (L) allele carriers taking selective serotonin reuptake inhibitors (SSRIs) reported fewer ADRs relative to short/short (SS) carriers. European L carriers taking SSRIs had lower ADR rates than S carriers. These results suggest the 5-HTTLPR polymorphism may serve as a marker for antidepressant outcomes in psychiatric disorders and may be particularly relevant to SSRI treatment among individuals of European descent.
KW  - 5-HTTLPR
KW  - genotype
KW  - pharmacogenetics
KW  - antidepressant
KW  - efficacy
KW  - tolerability
KW  - SLC6A4
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-252294
SN  - 2075-4426
VL  - 11
IS  - 12
ER  - 
TY  - JOUR
A1  - Righesso, L. A. R.
A1  - Terekhov, M.
A1  - Götz, H.
A1  - Ackermann, M.
A1  - Emrich, T.
A1  - Schreiber, L. M.
A1  - Müller, W. E. G.
A1  - Jung, J.
A1  - Rojas, J. P.
A1  - Al-Nawas, B.
T1  - Dynamic contrast-enhanced magnetic resonance imaging for monitoring neovascularization during bone regeneration — a randomized in vivo study in rabbits
JF  - Clinical Oral Investigations
N2  - Objectives
Micro-computed tomography (μ-CT) and histology, the current gold standard methods for assessing the formation of new bone and blood vessels, are invasive and/or destructive. With that in mind, a more conservative tool, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), was tested for its accuracy and reproducibility in monitoring neovascularization during bone regeneration. Additionally, the suitability of blood perfusion as a surrogate of the efficacy of osteoplastic materials was evaluated.

Materials and methods
Sixteen rabbits were used and equally divided into four groups, according to the time of euthanasia (2, 3, 4, and 6 weeks after surgery). The animals were submitted to two 8-mm craniotomies that were filled with blood or autogenous bone. Neovascularization was assessed in vivo through DCE-MRI, and bone regeneration, ex vivo, through μ-CT and histology.

Results
The defects could be consistently identified, and their blood perfusion measured through DCE-MRI, there being statistically significant differences within the blood clot group between 3 and 6 weeks (p = 0.029), and between the former and autogenous bone at six weeks (p = 0.017). Nonetheless, no significant correlations between DCE-MRI findings on neovascularization and μ-CT (r =−0.101, 95% CI [−0.445; 0.268]) or histology (r = 0.305, 95% CI [−0.133; 0.644]) findings on bone regeneration were observed.

Conclusions
These results support the hypothesis that DCE-MRI can be used to monitor neovascularization but contradict the premise that it could predict bone regeneration as well.
KW  - animal experimentation
KW  - bone regeneration
KW  - multiparametric magnetic resonance imaging
KW  - neovascularization, physiologic
KW  - tissue engineering
KW  - translational medical research
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-307614
SN  - 1432-6981
SN  - 1436-3771
VL  - 25
IS  - 10
ER  - 
TY  - JOUR
A1  - Dindas, Julian
A1  - Scherzer, Sönke
A1  - Roelfsema, M. Rob G.
A1  - Meyer, Katharina von
A1  - Müller, Heike M.
A1  - Al-Rasheid, K. A. S.
A1  - Palme, Klaus
A1  - Dietrich, Petra
A1  - Becker, Dirk
A1  - Bennett, Malcolm J.
A1  - Hedrich, Rainer
T1  - AUX1-mediated root hair auxin influx governs SCFTIR1/AFB-type Ca2+ signaling
JF  - Nature Communications
N2  - Auxin is a key regulator of plant growth and development, but the causal relationship between hormone transport and root responses remains unresolved. Here we describe auxin uptake, together with early steps in signaling, in Arabidopsis root hairs. Using intracellular microelectrodes we show membrane depolarization, in response to IAA in a concentration- and pH-dependent manner. This depolarization is strongly impaired in aux1 mutants, indicating that AUX1 is the major transporter for auxin uptake in root hairs. Local intracellular auxin application triggers Ca2+ signals that propagate as long-distance waves between root cells and modulate their auxin responses. AUX1-mediated IAA transport, as well as IAA- triggered calcium signals, are blocked by treatment with the SCFTIR1/AFB - inhibitor auxinole. Further, they are strongly reduced in the tir1afb2afb3 and the cngc14 mutant. Our study reveals that the AUX1 transporter, the SCFTIR1/AFB receptor and the CNGC14 Ca2+ channel, mediate fast auxin signaling in roots.
KW  - auxin
KW  - permeation and transport
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225368
VL  - 9
ER  - 
TY  - JOUR
A1  - Bernt, Alexander
A1  - Rangrez, Ashraf Y.
A1  - Eden, Matthias
A1  - Jungmann, Andreas
A1  - Katz, Sylvia
A1  - Rohr, Claudia
A1  - Müller, Oliver J.
A1  - Katus, Hugo A.
A1  - Sossalla, Samuel T.
A1  - Williams, Tatjana
A1  - Ritter, Oliver
A1  - Frank, Derk
A1  - Frey, Norbert
T1  - Sumoylation-independent activation of Calcineurin-NFAT-signaling via SUMO2 mediates cardiomyocyte hypertrophy
JF  - Scientific Reports
N2  - The objective of this study was to identify unknown modulators of Calcineurin (Cn)-NFAT signaling. Measurement of NFAT reporter driven luciferase activity was therefore utilized to screen a human cardiac cDNA-library (~10\(^{7}\) primary clones) in C2C12 cells through serial dilutions until single clones could be identified. This extensive screening strategy culminated in the identification of SUMO2 as a most efficient Cn-NFAT activator. SUMO2-mediated activation of Cn-NFAT signaling in cardiomyocytes translated into a hypertrophic phenotype. Prohypertrophic effects were also observed in mice expressing SUMO2 in the heart using AAV9 (Adeno-associated virus), complementing the in vitro findings. In addition, increased SUMO2-mediated sumoylation in human cardiomyopathy patients and in mouse models of cardiomyopathy were observed. To decipher the underlying mechanism, we generated a sumoylation-deficient SUMO2 mutant (ΔGG). Surprisingly, ΔGG replicated Cn-NFAT-activation and the prohypertrophic effects of native SUMO2, both in vitro and in vivo, suggesting a sumoylation-independent mechanism. Finally, we discerned a direct interaction between SUMO2 and CnA, which promotes CnA nuclear localization. In conclusion, we identified SUMO2 as a novel activator of Cn-NFAT signaling in cardiomyocytes. In broader terms, these findings reveal an unexpected role for SUMO2 in cardiac hypertrophy and cardiomyopathy, which may open the possibility for therapeutic manipulation of this pathway.
KW  - Calcineurin-NFATsignaling
KW  - activation
KW  - SUMO2
KW  - cardiac hypertrophy
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167525
VL  - 6
IS  - 35758
ER  - 
TY  - JOUR
A1  - Hardulak, Laura A.
A1  - Morinière, Jérôme
A1  - Hausmann, Axel
A1  - Hendrich, Lars
A1  - Schmidt, Stefan
A1  - Doczkal, Dieter
A1  - Müller, Jörg
A1  - Hebert, Paul D. N.
A1  - Haszprunar, Gerhard
T1  - DNA metabarcoding for biodiversity monitoring in a national park: Screening for invasive and pest species
JF  - Molecular Ecology Resources
N2  - DNA metabarcoding was utilized for a large‐scale, multiyear assessment of biodiversity in Malaise trap collections from the Bavarian Forest National Park (Germany, Bavaria). Principal component analysis of read count‐based biodiversities revealed clustering in concordance with whether collection sites were located inside or outside of the National Park. Jaccard distance matrices of the presences of barcode index numbers (BINs) at collection sites in the two survey years (2016 and 2018) were significantly correlated. Overall similar patterns in the presence of total arthropod BINs, as well as BINs belonging to four major arthropod orders across the study area, were observed in both survey years, and are also comparable with results of a previous study based on DNA barcoding of Sanger‐sequenced specimens. A custom reference sequence library was assembled from publicly available data to screen for pest or invasive arthropods among the specimens or from the preservative ethanol. A single 98.6% match to the invasive bark beetle Ips duplicatus was detected in an ethanol sample. This species has not previously been detected in the National Park.
KW  - biodiversity
KW  - DNA barcoding
KW  - invasive species
KW  - metabarcoding
KW  - monitoring
KW  - pest species
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-217812
VL  - 20
IS  - 6
SP  - 1542
EP  - 1557
ER  - 
TY  - JOUR
A1  - Hofrichter, Michaela A. H.
A1  - Mojarad, Majid
A1  - Doll, Julia
A1  - Grimm, Clemens
A1  - Eslahi, Atiye
A1  - Hosseini, Neda Sadat
A1  - Rajati, Mohsen
A1  - Müller, Tobias
A1  - Dittrich, Marcus
A1  - Maroofian, Reza
A1  - Haaf, Thomas
A1  - Vona, Barbara
T1  - The conserved p.Arg108 residue in S1PR2 (DFNB68) is fundamental for proper hearing: evidence from a consanguineous Iranian family
JF  - BMC Medical Genetics
N2  - Background:
Genetic heterogeneity and consanguineous marriages make recessive inherited hearing loss in Iran the second most common genetic disorder. Only two reported pathogenic variants (c.323G>C, p.Arg108Pro and c.419A>G, p.Tyr140Cys) in the S1PR2 gene have previously been linked to autosomal recessive hearing loss (DFNB68) in two Pakistani families. We describe a segregating novel homozygous c.323G>A, p.Arg108Gln pathogenic variant in S1PR2 that was identified in four affected individuals from a consanguineous five generation Iranian family.

Methods:
Whole exome sequencing and bioinformatics analysis of 116 hearing loss-associated genes was performed in an affected individual from a five generation Iranian family. Segregation analysis and 3D protein modeling of the p.Arg108 exchange was performed.

Results:
The two Pakistani families previously identified with S1PR2 pathogenic variants presented profound hearing loss that is also observed in the affected Iranian individuals described in the current study. Interestingly, we confirmed mixed hearing loss in one affected individual. 3D protein modeling suggests that the p.Arg108 position plays a key role in ligand receptor interaction, which is disturbed by the p.Arg108Gln change.

Conclusion:
In summary, we report the third overall mutation in S1PR2 and the first report outside the Pakistani population. Furthermore, we describe a novel variant that causes an amino acid exchange (p.Arg108Gln) in the same amino acid residue as one of the previously reported Pakistani families (p.Arg108Pro). This finding emphasizes the importance of the p.Arg108 amino acid in normal hearing and confirms and consolidates the role of S1PR2 in autosomal recessive hearing loss.
KW  - 3D modeling
KW  - autosomal recessive non-synstromic hearing loss
KW  - DFNB68
KW  - mixed hearing loss
KW  - whole exome sequencing
KW  - S1PR2
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-175755
VL  - 19
IS  - 81
ER  - 
TY  - JOUR
A1  - Otto, C.
A1  - Schmidt, S.
A1  - Kastner, C.
A1  - Denk, S.
A1  - Kettler, J.
A1  - Müller, N.
A1  - Germer, C.T.
A1  - Wolf, E.
A1  - Gallant, P.
A1  - Wiegering, A.
T1  - Targeting bromodomain-containing protein 4 (BRD4) inhibits MYC expression in colorectal cancer cells
JF  - Neoplasia
N2  - The transcriptional regulator BRD4 has been shown to be important for the expression of several oncogenes including MYC. Inhibiting of BRD4 has broad antiproliferative activity in different cancer cell types. The small molecule JQ1 blocks the interaction of BRD4 with acetylated histones leading to transcriptional modulation. Depleting BRD4 via engineered bifunctional small molecules named PROTACs (proteolysis targeting chimeras) represents the next-generation approach to JQ1-mediated BRD4 inhibition. PROTACs trigger BRD4 for proteasomale degradation by recruiting E3 ligases. The aim of this study was therefore to validate the importance of BRD4 as a relevant target in colorectal cancer (CRC) cells and to compare the efficacy of BRD4 inhibition with BRD4 degradation on downregulating MYC expression. JQ1 induced a downregulation of both MYC mRNA and MYC protein associated with an antiproliferative phenotype in CRC cells. dBET1 and MZ1 induced degradation of BRD4 followed by a reduction in MYC expression and CRC cell proliferation. In SW480 cells, where dBET1 failed, we found significantly lower levels of the E3 ligase cereblon, which is essential for dBET1-induced BRD4 degradation. To gain mechanistic insight into the unresponsiveness to dBET1, we generated dBET1-resistant LS174t cells and found a strong downregulation of cereblon protein. These findings suggest that inhibition of BRD4 by JQ1 and degradation of BRD4 by dBET1 and MZ1 are powerful tools for reducing MYC expression and CRC cell proliferation. In addition, downregulation of cereblon may be an important mechanism for developing dBET1 resistance, which can be evaded by incubating dBET1-resistant cells with JQ1 or MZ1.
KW  - Cancer
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202451
VL  - 21
IS  - 11
ER  - 
TY  - JOUR
A1  - Müller, Anna A.
A1  - Dolowschiak, Tamas
A1  - Sellin, Mikael E.
A1  - Felmy, Boas
A1  - Verbree, Carolin
A1  - Gadient, Sandra
A1  - Westermann, Alexander J.
A1  - Vogel, Jörg
A1  - LeibundGut-Landmann, Salome
A1  - Hardt, Wolf-Dietrich
T1  - An NK Cell Perforin Response Elicited via IL-18 Controls Mucosal Inflammation Kinetics during Salmonella Gut Infection
JF  - PLoS Pathogens
N2  - Salmonella Typhimurium (S.Tm) is a common cause of self-limiting diarrhea. The mucosal inflammation is thought to arise from a standoff between the pathogen's virulence factors and the host's mucosal innate immune defenses, particularly the mucosal NAIP/NLRC4 inflammasome. However, it had remained unclear how this switches the gut from homeostasis to inflammation. This was studied using the streptomycin mouse model. S.Tm infections in knockout mice, cytokine inhibition and –injection experiments revealed that caspase-1 (not -11) dependent IL-18 is pivotal for inducing acute inflammation. IL-18 boosted NK cell chemoattractants and enhanced the NK cells' migratory capacity, thus promoting mucosal accumulation of mature, activated NK cells. NK cell depletion and Prf\(^{-/-}\) ablation (but not granulocyte-depletion or T-cell deficiency) delayed tissue inflammation. Our data suggest an NK cell perforin response as one limiting factor in mounting gut mucosal inflammation. Thus, IL-18-elicited NK cell perforin responses seem to be critical for coordinating mucosal inflammation during early infection, when S.Tm strongly relies on virulence factors detectable by the inflammasome. This may have broad relevance for mucosal defense against microbial pathogens.
KW  - NK cells
KW  - Salmonella Typhimurium
KW  - mucosal inflammation
KW  - diarrhea
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167429
VL  - 12
IS  - 6
ER  - 
TY  - JOUR
A1  - Müller, P.A.
A1  - Bröcker, E.B.
A1  - Klinker, E.
A1  - Stoevesandt, J.
A1  - Benoit, S.
T1  - Adjuvant treatment of recalcitrant Bullous pemphigoid with immunoadsorption
JF  - Dermatology
N2  - Elimination of pathogenic autoantibodies by immunoadsorption (IA) has been described as an effective adjuvant treatment in severe bullous autoimmune diseases, especially in pemphigus. There is much less experience in the treatment of bullous pemphigoid (BP). BP was diagnosed in a 62-year-old Caucasian woman presenting a pruritic rash with multiple tense blisters. Standard treatments with topical and oral corticosteroids, steroid-sparing agents including dapsone, azathioprine, mycophenolate mofetil (MMF) and intravenous immunoglobulins were ineffective or had to be discontinued due to adverse events. An immediate clinical response could be achieved by two treatment cycles of adjuvant protein A immunoadsorption (PA-IA) in addition to continued treatment with MMF (2 g/day) and prednisolone (1 mg/kg/day). Tolerance was excellent. Clinical improvement remained stable after discontinuation of IA and went along with sustained reduction of circulating autoantibodies. Our data demonstrate that PA-IA might be a safe and effective adjuvant treatment in severe and recalcitrant BP.
KW  - Bullous pemphigoid
KW  - Immunoadsorption
KW  - Immunoapheresis
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196620
SN  - 1018-8665
SN  - 1421-9832
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 224
IS  - 3
SP  - 224
EP  - 227
ER  -